The Phase-Amplitude Coupling Induced by Drug Cues in Individuals With Methamphetamine Use Disorder During Withdrawal

Substance use disorder (SUD) is a major global health challenge, with methamphetamine use disorder (MUD) being particularly severe due to its high addictiveness and relapse rate. The neurophysiological basis of MUD remains unclear.

This study investigated cross-frequency coupling in 46 male abstinent individuals with MUD to examine multi-scale neural information integration. Electroencephalography (EEG) was recorded during exposure to drug-related and neutral cues. Phase-amplitude coupling (PAC) and phase slope index (PSI) were used to assess local and directed network connectivity, respectively.

Cue-induced PAC enhancements correlated significantly with craving: left prefrontal AF3 PAC (10-14 Hz/60-82 Hz) was negatively correlated (r = -0.34 to -0.63, p < 0.05), whereas centro-parietal CP2 PAC (6-11 Hz/74-94 Hz) was positively correlated (r = 0.33-0.49, p < 0.05). PSI analysis showed reversed prefrontal-to-occipital flow (p < 0.05) and disrupted centro-parietal to sensorimotor connectivity (p < 0.05) under drug cues.

Drug-related cues may exacerbate craving by weakening top-down prefrontal regulation and amplifying bottom-up sensorimotor drive. PAC and PSI represent promising cue-reactive predictive biomarkers for evaluating the neural substrates of drug cue-induced craving severity in individuals with MUD.